Nonsteroidal anti-inflammatory agents such as diclofenac, difenpiramide, fenbufen, flufenamic acid, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, piroxicam, suprofen and tiaprofenic acid, are widely used to relieve mild to moderate pain, for fever, and to treat inflammatory conditions. Sodium diclofenac, for example, is particularly effective for relief of musculoskeletal and joint disorders such as rheumatoid arthritis, an autoimmune disease, osteoarthritis and ankylosing spondilitis; periacicular disorders such as bursitis and tendinitis; soft-tissue disorders such as sprains and strains, and other painful conditions such as renal colic, acute gout, dysmenorrhoea, and for relieving pain following some surgical disorders. The NSAIDs are non-habit forming drugs and thus offer a significant advantage over traditional opioid-based drugs; furthermore, as NSAIDs are by definition "nonsteroidal," the side effects commonly associated with oral administration of steroids are avoided as well. However, it is recognized that NSAIDs also exhibit some undesirable side effects, particularly at high dosages and/or with chronic oral administration. Generally, high dosages and chronic use of NSAIDs are associated with problems such as gastrointestinal and duodenal bleeding, ulceration and perforation.
In view of the advantages of NSAIDs over opioid-based drugs and steroidal agents, steps have been undertaken to minimize the drugs' adverse effects. In one approach, NSAIDs have been administered locally, such as by injection, by topical administration of, for example, an ointment or cream, by use of a transdermal patch, or by an inhalation device. Although local administration is desirable, administration of an effective amount of the active agent is difficult or inconvenient. In another approach to reduce the adverse effects of NSAIDs, the agents are ingested after food or milk, or are taken in combination with antacids, histamine H.sub.2 -receptor antagonists, omeprazole, or sucralefate.
In yet another approach to reduce the undesirable gastrointestinal effects resulting from the oral administration of NSAIDs, the agents have been co-administered with some prostaglandins, particularly "E-series" prostaglandins such as PGE.sub.1, PGE.sub.2, misoprostol, and derivatives thereof; see, e.g., U.S. Pat. Nos. 3,781,429 to Partridge, 3,927,213 to Lippman, 3,928,588 to Robert, and 5,015,481 to Franz et al. Administration of a prostaglandin with an NSAID has been shown to reduce the ulcerogenicity of the NSAID. However, prostaglandins are unstable compounds and degrade readily in the presence of NSAIDs, thus requiring a stabilizing agent such as hydroxypropyl methylcellulose (HPMC) or polyvinylpyrrolidone (PVP) which can, in turn, lessen the activity of an NSAID. See, for example, U.S. Pat. No. 4,301,146 to Sanvordeker, which discloses prostaglandin E-type compounds stabilized with hydroxypropyl methylcellulose or polyvinylpyrrolidone before being pressed into tablets, U.S. Pat. No. 3,954,787 to Monkhouse, which discloses that lyophilized compositions of prostaglandin E and sodium chloride, cyclodextrin or polyvinylpyrrolidone are stable, and U.S. Pat. No. 5,015,481 to Franz et al., which discusses the destabilization of prostaglandins in the presence of the NSAIDs diclofenac and piroxicam.
There is, accordingly, a need in the art to provide a composition for administering an NSAID wherein the undesirable gastrointestinal side effects of the drug are minimized but wherein the drug's therapeutic effectiveness is maintained. The present invention is addressed to the aforementioned need in the art and provides a stabilized pharmaceutical composition of an NSAID and a prostaglandin, i.e., a composition in which the prostaglandin is stabilized and the efficacy of the NSAID is maintained.